Discordant association of the CREBRF rs373863828 A allele with increased BMI and protection from type 2 diabetes in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand

Abstract

Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.

Population specific reference panels are crucial for the genetic analyses of Native Hawai’ians: an example of theCREBRFlocus

“…We demonstrated the urgent need of having proper reference sequences in order to explore population-specific variants in diverse populations by using rs373863828 in CREBRF as an example in this study. We replicated the increasing effect of the derived allele of this variant on anthropometric and adiposity traits in Native Hawai'ians, and its protective effect on type II diabetes, consistent with reports in other populations from the Pacific Islands 11,15,16 . When examining more refined measure of body fat distribution, we also found the derived allele to be associated with increasing total fat mass and whole body fat percentage, even though we only have data available on ~300 Native Hawai'ians.…”

“…Consistent with this observation is the lowered derived allele frequency in Native Hawai'ians (approximately 13% in relatively unadmixed Native Hawai'ians, vs. 26% in Samoans). While the settlement in Polynesia is believed to have occurred in a west-to-east direction across the Pacific, the derived allele is also found in lower frequency (~2 to 19%) in other populations in Pacific, including Tongans and New Zealand Maori living west of Samoa [12][13][14][15] . It is unclear whether the difference of allele frequencies among the Pacific Islanders is mostly attributed to the differences in selection strength, the bottleneck and genetic drift in the founding Polynesians, different admixture histories, or some combinations of the above.…”

“…Rs373863828 was found to have a large effect on body mass index (BMI) as well as on a number of other adiposity, metabolic, and anthropometric traits in Samoans 11 . Despite an estimated 26% allele frequency in Samoans, the derived allele is only segregating in the few Pacific Islands populations and not found elsewhere in the world [12][13][14][15][16] . Because of a lack in Polynesian haplotypes in publicly accessible sequencing databases (e.g.…”

A missense variant in CREBRF is associated with taller stature in Samoans

“…Recently, we identified a novel association between a missense mutation (rs373863828, c.1370G>A, p.R457Q) in the gene for transcription factor CREB3 regulatory factor ( CREBRF ) and body mass index (BMI) in individuals of Polynesian ancestry (Krishnan et al, 2018; Minster et al, 2016) Despite fine-mapping and functional work suggesting the causal variant of this association is rs373863828 (Minster et al, 2016), the biological mechanism through which CREBRF operates to affect BMI is still unknown.…”

“…The rs373863828 variant is common in Samoans (minor allele frequency, MAF=0.259), but is very rarely seen in individuals without Pacific Island ancestry (gnomAD MAF for all populations=3.53 × 10 −5 ; accessed 12 April 2019). However, this variant is polymorphic and associated with BMI in other Pacific Island populations including New Zealand Māori, Pukapukans, and other Polynesians (Krishnan et al, 2018).…”